1. Field of the Invention
The present invention relates to novel compounds, a preparation thereof and a pharmaceutical composition comprising the same for the alleviation, prophylaxis or treatment of osteoporosis. More particularly, the present invention relates to the novel compounds inhibiting differentiation of osteoclasts, a preparation thereof and a pharmaceutical composition comprising the same for the alleviation, prophylaxis or treatment of osteoporosis.
2. Description of the Related Art
Osteoporosis is a common disease around the world, with about two hundred million persons worldwide affected thereby or suffering from low bone mass. In osteoporosis, the bone mass is reduced and the bone microarchitecture deteriorates, resulting in weakened bones. Thus, osteoporosis is a disease of the bone characterized by the increased risk of fracture particularly in the backbone, the hip joint, the carpal, the humerus, and the pelvis.
A. Bone
The three main types of cells constituting the bone are osteoblasts, osteocytes and osteoclasts. Osteoblasts are anabolic: they stimulate new bone formation by synthesizing osteoid, the organic portion of the bone matrix, which mineralizes to become bone. Osteoblasts arise from osteoprogenitor cells located in the bone marrow. The formation of osteoid completes within a relatively short period of time, typical 6˜12 hours, whereas it takes a much longer time, i.e. 1˜2 months, to accomplish the subsequent mineralization. After formation of the bone, osteoblasts become entrapped in the bone matrix to become osteocytes.
Osteocytes are the most numerous cells found in bone. It has been proposed that they play an integral role in the action of mechanostat, that is, in transmitting local strain information to enable the bone multicellular unit to adjust the bone content in response to the local need. Osteoclasts are large, multinucleated cells that are formed by the fusion of cells of the monocyte-macrophage cell line. Osteoclasts are catabolic: they destroy constituents of the bone through the action of lysosomal enzymes at specific sites. Pathway associated with receptor activation of nuclear factor κB ligand (RANKL) functions as a key factor in osteoclast differentiation and activation.
In addition, the RANKL/RANK/OPG system is currently regarded as the most important route for the regulation of bone resorption. RANKL is a member of the tumor necrosis factor (TNF) cytokine family, and is expressed by osteoblasts. RANKL binds to the membrane bound receptor RANK of osteoclasts to promote the differentiation of osteoclasts from hematopoetic cells. Promotion of expression of RANKL is induced by hormones such as parathyroid hormone (PTH), calcitriol and prostaglandin. Osteoclasts secret soluble receptor called osteoprotegerin (OPG). OPG is an important regulating factor as a potent antagonist in formation of osteoclasts which bind to RANKL to inactivate. OPG is stimulated by estrogen.
B. Factors for Osteoporosis
Osteoporosis is classified when the bone mineral density is 2.5 or lower or T-score (T-score is the number of standard deviations the bone mineral density measurement is above or below the young normal reference mean bone mineral density) is −2.5 or lower. Bone loss increases with age, starting in the forties or fifties. At this time, osteoporosis occurs because bone resorption by osteoclasts is increased, and bone formation by osteoblasts is decreased. In women, bone loss is accelerated by menopause. Peak bone mass is usually reached by the age of 30, acting as an important determinant for the subsequent bone mass. Peak bone mass is largely determined by the genetic makeup and is affected by other factors including nutrition, particularly the intake of calcium and vitamin D, hormone state, body exercise, smoking, low body weight, the time of adolescence, etc.
Estrogen deficiency is considered to be a decisive factor for osteoporosis, which is inferred from the highest prevalence of osteoporosis in post-menopausal women who experience natural decreases in estrogen levels. Estrogen deficiency following menopause is correlated with an increase in bone resorption, giving rise to rapid and persistent bone loss. Estrogen plays an important role in bone resorption in males as well as females, and has an effect on the achievement of peak bone mass. In addition, osteoporosis in senile males is more greatly associated with a low estrogen level than with a low androgen level.
Calcium deficiency has early been pointed out as a primary cause of osteoporosis (particularly in the elderly). Calcium deficiency, whether due to low calcium intake or hypercalcuria, increases PTH (parathyroid hormone) secretion and bone resorption. PTH, which is a peptide composed of 84 amino acids, is essential for the regulation of calcium homeostasis and its serum level is inversely correlated with calcium concentration in bone. Calcium binds to the calcium-sensing receptor in parathyroid cells to influence the release of PTH. PTH enhances renal calcium reabsorption, intestinal calcium uptake and bone remodeling. Vitamin D deficiency and secondary hyperparathyroidism are often occurred in the elderly, contributing to senile osteoporosis. Secondary hyperparathyroidism occurs when there is relative insufficiency of vitamin D, that is, where the levels of the circulating form, 25-hydroxy vitamin D, fall below 30 ng/mL, suggesting that the target for vitamin D supplementation should be at this level or higher. The active hormonal form, 1,25-dihydroxy vitamin D (calcitriol), is not only necessary for intestinal absorption of calcium and phosphorus, but also exerts a tonic inhibitory effect on PTH synthesis, so that there are dual pathways that can lead to secondary hyperparathyroidism. Vitamin D deficiency and secondary hyperparathyroidism can contribute not only to accelerated bone loss and increasing fragility, but also to neuromuscular impairment that can increase the risk of falls.
C. Design of New Therapeutics for Osteoporosis
Medicines currently used for osteoporosis include bisphosphonates agents (allendronate, etidronate, etc.), hormonal agents (raloxifene), vitamin D agents, calcitonin agents and calcium agents, etc. Commonly, the medicines for osteoporosis are not likely to elicit patient compliance and persistent medicine intake. Oral bisphosphonates can induce upper gastrointestinal side effects, so that patients must take them together with a sufficient amount of water on an empty stomach and sit upright for 30˜60 minutes after the uptake of the medication, without ingesting foods or beverages. Thus, there are a lot of precaution for administration of medication. Also, there are concerns that long-term bisphosphonate use can induce excess ossification and an increase of micro-cracks in the bone by excessively inhibiting remodeling of and unable to recover the bone fracture and micro damage. Hormonal agents cause side effects as large as the therapeutic effects. PTH is required to be taken through a subcutaneous route every day and is expensive. Intake of calcium and vitamin D alone does not guarantee reliable pharmaceutical efficacy. Osteoporosis is not cured by short-term use of drugs, but its therapy requires the administration of medication over a long period of time. There is therefore the need for a novel medication that guarantees excellent pharmaceutical efficacy without engendering side effects even upon long-term use.